This is a request for continuation of a Research Scientist Award. My broadest objective are to understand why people take psychoactive drugs, what are usual and expected effects, and what might account for unexpected consequences. For examine, what is the role of tolerance and dependence in determining individual differences in drug use and effects. Individual projects study the pharmacokinetics and pharmacodynamics of cocaine administered by various routes, its interactions with other drugs and the characteristics of tolerance and dependence associated with subchronic cocaine administration and cocaine effects on the immune system. The role of nicotine in tobacco dependence is investigated with laboratory and clinical treatment studies. Characterization of abstinence, the pharmacokinetics and dynamics of nicotine and its metabolites and factors altering such effects is studied along with evaluation of treatments for tobacco dependence. Cannabinoid studies investigate the relationship between the development of tolerance and dependence and changes in marijuana smoking. Whenever possible equal attention is given to psychological and behavioral measures, subjective mood reports, neurophysiological and neurochemical indices. In the clinical studies an attempt is made to understand relationships between behavioral, physiologic and pharmacologic variables. Biochemical, physiologic, neuroendocrinologic, behavioral and psychometric techniques are used to assess consequences of acute and subchronic drug administration. Recognizing that people only rarely limit their drug taking to a single drug or class of drugs, development and application of research strategies appropriate to the study of multiple classes of drugs rather than specialization in a particular methodology or drug class is a guiding philosophy. Where possible, mechanisms and explanations for individual differences in drug effects are emphasized. Relationships between naturally occurring and drug induced disorders for example anxiety states and schizophrenia or other psychosis remains a topic of interest. The studies are multidisciplinary in approach and involve only human subjects. They should further understanding of human psychoactive drug use and its health consequences.